Embryo quality assessment based on blastomere cleavage and morphology

Abstract

The present invention relates to a method and to a system for selecting embryos for in vitro fertilization based on the timing, and duration of observed cell cleavages and associated cell morphology. One embodiment of the invention relates to a method for determining embryo quality comprising monitoring the embryo for a time period, and determining one or more quality criteria for said embryo, wherein said one or more quality criteria is based on the extent of irregularity of the timing of cell divisions when the embryo develops from four to eight blastomeres, and/or wherein said one or more quality criteria is based on determining the time of cleavage to a five blastomere embryo (t5) and wherein t5 is between 48.7 hours and 55.6 hours, and/or wherein said one or more quality criteria is based on the ratio of two time intervals, each of said two time intervals determined as the duration of a time period between two morphological events in the embryo development from fertilization to eight blastomeres, and based on said one or more quality criteria determining the embryo quality.

1 . A method for determining human embryo quality comprising monitoring the human embryo for a time period after in vitro fertilization, and determining one or more quality criteria for said human embryo, wherein said one or more quality criteria is based on a ratio determined from two or more time intervals, each of said time intervals determined as the duration of a time period between two morphological events in the human embryo development from fertilization to eight blastomeres, and based on said one or more quality criteria determining the human embryo quality. 
     
     
         2 . (canceled) 
     
     
         3 . The method according to  claim 1 , wherein the human embryo quality is a quality relating to implantation success. 
     
     
         4 . The method according to  claim 1 , wherein said one or more quality criteria are combined with one or more exclusion criteria for deselecting and/or excluding human embryos with a low probability of implantation success. 
     
     
         5 . The method according to  claim 4 , wherein an exclusion criterion is selected from the group comprising:
 that cc2 and/or cc3 is less than 5 hours;   that t2 is greater than 31.8 hours;   that t5 is less than 49 hours;   that cc2b is greater than 13.1 hours;   that cc3 is greater than 17.6 hours;   that s2 is greater than 2.1 hours; and   that s3 is greater than 13.8 hours.   
     
     
         6 . The method according to  claim 1 , wherein each of said time intervals is based on one parameter, or subtraction of two parameters, selected from the group of t2, t3, t4, t5, t6, t7 and t8. 
     
     
         7 . The method according to  claim 1 , wherein said morphological events are selected from the group of fertilization, initiation of a blastomere cleavage and completion of a blastomere cleavage. 
     
     
         8 . The method according to  claim 1 , wherein said ratio of time intervals is selected from the group of:
 cc2/cc2 — 3=(t3−t2)/(t5−t2),   cc3/cc2 — 3=(t5−t3)/(t5−t2),   cc3/t5=1−t3/t5,   s2/cc2=(t4−t3)/(t3−t2),   s3/cc3=(t8−t5)/(t5−t3), and   cc2/cc3=(t3−t2)/(t5−t3).   
     
     
         9 . The method according to  claim 1 , wherein a quality criterion is selected from the group comprising a:
 determination of cc2/cc2 — 3=(t3−t2)/(t5−t2) and wherein said quality criterion is an indicator of high human embryo quality if cc2/cc2 — 3 between 0.41 and 0.47;   determination of cc3/t5=1−t3/t5 and wherein said quality criterion is an indicator of high human embryo quality if cc3/t5 is between 0.26 and 0.28;   
       8;
 determination of s2/cc2=(t4−t3)/(t3−t2) and wherein said quality criterion is an indicator of high human embryo quality if s2/cc2=(t4−t3)/(t3−t2) is less than 0.025; 
 determination of s3/cc3=(t8−t5)/(t5−t3) and wherein said quality criterion is an indicator of high human embryo quality if s3/cc3 is less than 0.18; 
 determination of cc2/cc3=(t3−t2)/(t5−t3) and wherein said quality criterion is an indicator of high human embryo quality if cc2/cc3 is between 0.72 and 0.88; 
 determination of the time for cleavage to an 8 blastomere human embryo, t8 and wherein said quality criterion is an indicator of high human embryo quality if t8 is less than 57.2 hours; 
 determination of the second cell cycle length cc2=t3−t2 and wherein said quality criterion is an indicator of high human embryo quality if cc2 is less than 12.7 hours; 
 determination of cc2b=t4−t2 and wherein said quality criterion is an indicator of high human embryo quality if cc2b is less than 12.7 hours; 
 determination of the third cell cycle length cc3=t5−t3 and wherein said quality criterion is an indicator of high human embryo quality if cc3 is between 12.9 and 16.3 hours; 
 determination of cc2 — 3=t5−t3 and wherein said quality criterion is an indicator of high human embryo quality if cc2 — 3 is between 24 and 28.7 hours; 
 determination of the synchrony in division from a 2 blastomere human embryo to a 4 blastomere human embryo s2=t4−t3 and wherein said quality criterion is an indicator of high human embryo quality if s2 is less than 1.33 hours or less than 0.33 hours; and 
 determination of the synchrony in division from a 4 blastomere human embryo to a 8 blastomere human embryo s3=t8−t5 and wherein said quality criterion is an indicator of high human embryo quality if s3 is less than 2.7 hours. 
 
     
     
         10 - 13 . (canceled) 
     
     
         14 . The method according to  claim 1 , wherein said extent of irregularity of the timing of cell divisions when the human embryo develops from four to eight blastomeres is determined by calculating the maximum cleavage time for each blastomere when the human embryo develops from 4 to 5 to 6 to 7 and to 8 blastomeres. 
     
     
         15 . The method according to  claim 14 , wherein said quality criterion is an indicator of high human embryo quality if said maximum cleavage time is less than 1.5 hours. 
     
     
         16 . The method according to  claim 1 , wherein said extent of irregularity of the timing of cell divisions when the human embryo develops from four to eight blastomeres is determined by calculating the ratio between the maximum cleavage time for each blastomere when the human embryo develops from 4 to 5 to 6 to 7 and to 8 blastomeres and the duration of the total time period from 4 to 8 blastomeres; max(s3a,s3b,s3c)/s3. 
     
     
         17 . The method according to  claim 16 , wherein said quality criterion is an indicator of high human embryo quality if said ratio is less than 0.5. 
     
     
         18 .- 24 . (canceled) 
     
     
         25 . The method according to  claim 1 , wherein an exclusion criterion includes information of blastomere evenness at t2, information of multi nuclearity at the two blastomere stage and/or at the four-blastomere stage, and/or information of cleavage from one blastomere directly to three blastomeres. 
     
     
         26 .- 31 . (canceled) 
     
     
         32 . The method according to  claim 1 , wherein the human embryo is monitored in an incubator. 
     
     
         33 . The method according to  claim 1 , wherein the human embryo is monitored through image acquisition, such as image acquisition at least once per hour, preferably image acquisition at least once per half hour. 
     
     
         34 . A method for selecting a human embryo suitable for transplantation, said method comprising monitoring the human embryo as defined in  claim 1  to obtain a human embryo quality measure, and selecting the human embryo having the highest human embryo quality measure. 
     
     
         35 . A system for determining human embryo quality comprising an imaging system configured to monitor the human embryo for a time period after in vitro fertilization to determine the timing of cell divisions when the human embryo develops from four to eight blastomeres, said system further having a computer configured to determine a one or more quality criteria for said human embryo, and to determine the human embryo quality based on said one or more quality criteria, wherein said one or more quality criteria is based on a ratio determined from two or more time intervals, each of said time intervals determined as the duration of a time period between two morphological events in the human embryo development from fertilization to eight blastomeres. 
     
     
         36 . (canceled)